Process for the preparation of an antiviral agent

Abstract

Racemic Feist's acid is treated with (R)-(+)-a-methylbenzylamine to yield (1R-trans)-3-methylenecyclopropane-1,2-dicarboxylic acid, (R)-a-methylbenzylamine (1:1) salt. This salt can then be converted to (1R-trans)-3-methylene-1,2-cyclopropanedicarboxylic acid, dimethyl ester which is an intermediate in the preparation of the antiviral agent Ä1R-(1a,2b,3a)Ü-2-amino-9-Ä2,3-bis(hydroxymethyl)cyclobutylÜ-1,9-dihyd ro-6H-purin-6-one. The improved process also enables the recovery of racemic Feist's acid from the resolution.

What is claimed is: 
     
       1. The process of recovering racemic (trans)-3-methylene-1,2-cyclopropanedicarboxylic acid from the reaction of (trans)-3-methylene-1,2-cyclopropanedicarboxylic acid with (R)-(+)-α-methylbenzylamine which comprises: a) reacting (trans)-3-methylene-1,2-cyclopropanedicarboxylic acid with (R)-(+)-αmethylbenzylamine in the presence of isopropanol and water at an elevated temperature;   b) concentrating the mother liquor from the reaction of step (a) to give a semi-solid residue;   c) the semi-solid residue from step (b) is taken up in isopropanol and heated to give a suspension which is extracted with ethyl acetate, filtered and dried to give (1S-trans)-3-methylenecyclopropane-1,2-dicarboxylic acid, (R)-α-methylbenzylamine (1:1) salt;   d) treating the partially resolved salt product from step (c) with aqueous sodium hydroxide and toluene and separating the aqueous and organic phases; and   e) heating the aqueous phase from step (d) to about 100° C. for about 18 hours, cooling to room temperature, adjusting the pH to about 2, extracting with ethyl acetate, and drying the organic fractions to recover racemic (trans)-3-methylene-1,2-cyclopropanedicarboxylic acid.